DRUG AFFECTING

CARDIOVASCULAR FUNCTION
Peter Kabo
Drug Affecting Cardiovascular Function

Anti hypertensive agents

Drugs used for the treatment of myocardial ischemia (anti

angina agents)

Pharmacological treatment of heart failure

Ant arrhythmic drugs

Physiology & pathophysiology of the cardiovascular system

Hypertensions

Coronary Artery Disease

Heart failure

Arrhythmia
 Jantung
Pembuluh darah
Sistem konduksi
• Automatisasi Tunika Antima
• Vasoaktif sub
Miokard
• Kontraktilitas (hukum starling) Tunika Media
Katup • Elastisitas
• Ao, pul. Mitral. Trikomidal

Artery Coroner
• Lumen
• Driving Pressure
ANATOMI SSO
 FAAL SSO

• Conservative
Parasimpatis • Reservation Acetyl choline

• Fight
Sympathies • Flight reaction Adrenaline/nor adrenaline

Transmisi Neurohormonal
Respon Efektor terhadap perangsangan SSO
Organ Resptor Respon Perangsang Respon Perangsang
Adrenergik Kolinergik

Jantung
Nodus SA β1 Nadi ↑ Nadi ↓
AV
β1 Kontraktilitas ↑ Kontraktilitas ↓
Atrium/ Ventrikel otot
β1 Konduksi ↑ Kondulsi ↓ ↓
Sist – konduksi
β1

Arteri & Vena α1 & α2 Konstriksi ?

β2 Dilatasi
Paru-paru
Otot bronkus + trankea
Kelenjar bronkus β2 Relaksasi Konstriksi
Sel mast Sekresi ↑ ↑
α2/β2 Sekresi ↓ / ↑
β2 Mediator inflam ↓
Sal cerna
Otot pls lambung & usus α1 & α2 Relaksasi Kontraksi
Otot Sfingter β2 Relaksasi
Kelenjar α1 Kontraksi Relaksasi
α2 Sekresi ↓ Sekresi ↑ ↑
Ginjal
Sekresi renin α1 ↓ -
β1 ↑
Kandung kemih
Otot detrusor β2 Relaksasi Kontraksi
Trigon & Sfingter α1 Kontraksi Relaksasi

Uterus α1 Kontraksi (hamil) Bervariasi

β2 Relaksasi
Prostat α1 Kontraksi
Mata α1 Midriasis Miosis
Hati α1, β 2 Glikogenolisis & -
glikoneogenesis
Pankreas α2 Sekresi insulin ↓
Sel β β2 Sekresi insulin ↓

Sel lemak β3 Lipolisis ↑ ↑

Kelenjar liur α1 Sekresi ↑ Sekresi ↑
Transmisi Adrenergik

Fenilalanin
↓ Hidroksiterase
Tirosin Hidroksilase
↓
Dopa Dekarboksilase
↓ β Hidroksilase
Dopamin
↓ Metiltrasferase
Noradrenalin
↓
Adrenalin
↓ ↓ Comt
↓ Normetanefrin
Metanefrin
3 – metoksi 4 –hidroksi femilglikol asam 3, 4 –
dihidroksi mandelat
 Denervasi kurase
Reseptor • Langley (1878)
Nikotin respon

Agonis • Obat yang menimbulkan respon

• Obat yangmenghambat respon yang

Antagonis ditimbulkan Agonis

Muskarinik
Asetilkolin
(M)

Nikotinik
(N)

α
Noradrenalin
Adrenalin
Isoprenalin

β
Anti Hypertensive Agents

Diuretics

Sympatholytic drugs

Vasodilators

Ca++ Channels Blockers

Angiotensin Converting Enzyme Inhibitors (ACE-I)

• Angiotensin II Receptor Antogonits
 Diuretics

• Hydrochlorothiazide (hct) 50 mg, 25 mg/ tab

Thiazides & related agents: • Chlorthalidone (hygrodone 50 mg/ tab)
• Indapamide (Natrilix SR 1,5 mg/ tab)

• Furosemide (Lasix 20 mg/ amp, 40 mg/ tab)

Loop diuretics
• Bumetanide

• Spironolactone (Aldactone 25mg, 50 mg, 100 mg)

K ± sparing diuretics
• Amilorita
 Pharmacological Effects Therapeutic uses
↑ Diuresis ↓ CO Oedema
↓ Na+ Excretion ↓ α1 receptor sensitivity ↓BP
Hypertension
↓ Uric acid excretion
Congestive Heart Failure
↑ K+ excretion (except spironolactone)

Adverse effect Diuretic Resistance

Hypo kalemia
1Bed Rest
Hyper uricemia

Hyoerglycemia
Increase dose

Ototokicity (loop diuretics) Administration of smaller doses more

frequently
↑ LDL, Trigliceride & ↓ HDL – cholesterol
Combination therapy
Gynecomastia (Spironolactone) Hyper K+

(NSAID, β Blocker & ACE-I)

Sexual impotence
Sympatholytic agents (Anti Adrenergic)

Central acting agents (methyldopa, clonidine)

Adrenergic neuron blocking agents

β – adrenergic antagonists (β – blockers)

α – adrenergic antagonists (α – blockers)

Mixed α & β – adrenergic antagonists (Labetolol, Carvedilol)

α-methyldopa (Dopamet 250 mg/tab)

↓
α-methyl dopamine
↓
α-methyl Noradrenaline

Pharmacological Effects:

↓ Sympathetic tone
• ↓ Cardiac output
• ↓ Peripheral resistance
• ↓ Myocardial contractility
• ↓ Heart rate
• ↓ Renin secretion
Prazosin (Minipress, 1 & 2 mg/tab)

Terazosin (Hytrin, 1 & 2 mg/tab)

Indication
Doxazosin (Cardura, 1 & 2 mg/tab)
Hypertension

Vasospastic disorders
Pharmacological Effects

Vasodilatation
Adverse Effects
• ↓ Arterial resistence
• ↓ Venous capaetance
First dose effect
↓ Triglyceride
Postural hypotension
↓ LDL Cholesterol

↓ HDL Cholesterol

↓ Resistance in trigone muscle – BPH – of

bladder and urethra
Isprenalin
Propanolol
Atenolol
Metoprolol
Bisoprolol
Timolol
Pindolol
 Bio Metabolis
Availibilita me lintas
Kardioselektif ISA s Oral (%) I (Hati) t1/2 (jam)

ACEBUTOLOL + + 30 - 50 + 3

METOPROLOL + - 40 - 50 + 3-6

ATENOLOL + - 40 - 60 - 6-8

BISOPROLOL +++ - 90 10% 11

PROPANOLOL - - 25 - 35 + 2-6

PINDOLOL - ++ 95 - 100 - 3-4

OKSPRENOLOL - + 25 - 50 + 2

SOTALOL - - 90 - 100 - 10 - 15

TIMOLOL - - 50 - 75 + 4-5

LABETOLOL (Alfa blocker) - + 25 + 5-8

CARVEDILOL
 Farmakodinamik indikasi Efek samping

Sistem (-) inotropik Takikardi Gagal jantung

kardiovaskular (-) kronotropik Takiaritmia Bradikardi
↓ resistensi perifer Hipertensiangina
(non-selektif) pektoris
↓ sekresi renin Turunkan TD Infark miokard
↓ cardiak output HOCM
↓ resistensi perifer Feokromasitoma
(pengguna kronis) Tirotoksikosis
Glaukoma

Saluran nafas Bronkokonstriksi Bronkospasme

Efek metabolik ↓ Asam lemak Hipertrigliserid

↓ Trigliserida Hipoglikemi
↓ HDL !! Putus obat
↓glikogenolisis
 Penghambat saraf adrenergik
Mekanisme kerja

• Mongosongkan katekolamin di ujung saraf adrenergik

Farmakodinamik
• Cardiac output ↓
• Resistensi perifer ↓

Indikasi
• Hipertensi

Efek samping
• Depresi psikotik

Clonidine

Methyl Dopa

Negative Feed back mechanism

Calcium Channel Blockers (CCB)
Golongan Dihidropiridin
• Nifedipin
• Amlodipin
• Felodipin
• Nikardipin
• Nimodopin

Benzodtiazepin
• Diltiazem

Difenalkilamin
• Verapamil

Relative Cardiovascular Effects

Vasodilatasi Supression of
Contractility Automaticity Conduction
Nifedipin 5 1 1 0
Diltiazem 3 2 5 4
Verapamil 4 4 5 5
 ANGIOTENSIN CONVERTING ENZYME (ACE) - INHIBITORS

Pharmacodynamic
Adverse effect

Bradikinin system Angiotensin system Cough

Angioedema
Kinino gen Angitensinogen
Hyper K++
Prelipitating renal failure
Endothelium
Applets anemia
Bradykinine Angiotensin I Dysgensia

Prostaglandin ACE-I
NO
Inactive Angiotensin II
peptide Na+ reabsorbsion
↑ Sympathetic activity
Growth (cardiac remodeling
vascular hyperthrophy)

G Angiotensin receptor antagonists

PLC
AT AT1 - antagonists
2
Antigrowth
Losartan
Apoptosin
DAG IP3 Vasodilatory Valsartan

Proteinkinase C Irbesartan
Candesartan
Contraction
 PENGHAMBAT ACE & ANGIOTENSIN RECEPTOR ANTAGONIST

Sel
Angitensoinogen
juxtaglomerolus
Renin
Bradikinin
AI
Non - ACE-I
ACE
AI ACE
Peptide maktif

Vasokinstriksi ↑ Aldosteron

Mekanisme Kerja ACE-I Efek samping:

↓ aktivitas sistem simpatis Batuk kering
↓ AII Udem Angioneurotik
First dose hipotensi
↓ Sekresi Aldosteron
Hiper K++
↓ Atrial Natriuric Factor
↓ Prostaglandin
 Angiotensin antagonis:
Losartan
Valsartan (Diovan)
Kegunaan
:
Hipertensi ringan s/d sedang
Preparat
(+) gagal jantung
LVH Captopril (Capoten) 25 mg/ tab
DM Enalapril (Inoprilat) 5 mg/ tab

Lisinopril (Zestril) 5 mg/ tab

Perindopril (Prexum) 4 mg/ tab

Ramipril (Triatec) 5 mg/ tab

ACE - Inhibitors
Sulfhydryl Containing:

•Captopril
•Zefenoprilat

Non- Sulfhydryl Containing:

• Enalaprilat Benazeprilat
• Lisinopril Cilaprilat
• Perindoprilat Delaprilat
• Quinaprilat Spiraprilat
• Ramiprilat Trandolaprilat

Phophoryl containing:

• Fosinoprilat

Pharmacokinetic:

• Lipid solubility
• Cone max
•T½
• T max
• AUC
 Pharmacological Treatment of Hypertension
Compelling indication & drug of choice (except contraindication)

Diabetes (+ protein urea)

• ACE-I
Heart Failure
• ACE-I, Diuretics
First line:
Isolated systolic HT
1. Diuretics
• Diuretics, Ca++ antagonists 2. β blocker
Myocardial infarction
• β-blockers, ACE-I
Angina Pectoris
• β-blockers, Ca++ antagonists
Dyslipidemia
• α blockers
Hyperthyroidism
• β-blockers
Osteoporosis
• Thiazide
Essential tremor
• β-blockers (non-selective)
Benign Prostate hypertrophy
• α blockers
Renal insufficiency
• ACE-I
 VASODILATORS

Arterial (Hydrolazine, Minoxidile)

Arterial & Venous (Na+ - Nitroprusside)

ANGINA PECTORIS

Arnil nitrat

Nitro gliserin

(Gliseril trinitrat = GTN)

Isosorbid Di-Nitrat
• (ISDN)

Isosorbid 5 – Mononitrat

Penta Eritritol Tetranitrat

Eritritil Tetranitrat
Mekanisme kerja

B
M S P T V
Nitrat 2

Endotel

EDRF NO?)

GS

GMP
Toleransi - SH
CGMP

Relaksasi
Farmakokinetik :
Reabsorbsi Hati
• SL • Metabolit di
• Oral Sirkulasi Ginjal
• Topikal
• IV

Farmakodinamik :
Relaksasi otot polos pembuluh darah ↑ Supply

Koroner ↓ preload → ↓ Wall

+ stress
sistemik
Hipotensi
Sakit kepala
Refleks Takikardi

Indikasi Rebound fenomena

Kontraindikasi: Syok &Hipersensitif
Angina Pektoris
Miokard Infark
Gagal Jantung Kongestif
Cardiac Glicoside
William Withering (1789) Digitalis lanata (foxglove putih)
Digitalis purpura (foxglove ungu)

Farmakokinetik

Absorbsi (40 – 75%) • Kardenolit : Inti steroid → lipofilik

tergantung jenis • Inti lakton → hidrofilik

• Metabolit → usus → (reabsorbsi) → sirkulasi & lerohepatis

Metabolisme : Hati • (t ½ ↑)

Distribusi : Seluruh tubuh

terutama di jantung
Eliminasi : tanpa
perubahan melalui ginjal
 Farmakokinetik
Dosis (beban) digitalisasi • 0.75 – 1.5 mg (oral)
(loading dose) • 0.5 – 1.0 mg (I.V.)

Dosis pemeliharaan/ hari • 0.125 – 0.5 mg (oral)

(maintenance dose) • 0.25 mg (I.V.)

• 1.5 – 3 jam (oral)

Mula kerja
• 5 – 30 menit (I.V.)

• 4 – 6 jam (oral)
Efek maksimal
• 1.5 – 3 jam (I.V.)

Absorbsi intestinal • ± 75%

T½ • 1.6 hari

Kadar terapi • 0.5 – 2.0 mg/ml

Eliminasi • Ginjal
Sign & Symptoms of Cardiac Glycoside Toxicity
• Arterial + ventricular Ectopic
Cardiac • SA & AV node conduction
disturbances
(bradyarrhytmias) Drug interaction with Digoxin

• Anorexia, Nausea, vomiting,

Gastrointestinal Abdominal pain
Change in
drug
digoxin level
• Blurred or yellow vision,
Visual Cholestyramine,
halos
Kaolin – peptin,
Neomylin,
Sulfazolazin, Bram ↓
• Delirium, fatigue, malaise, Antacid, Albuterol,
Thyroxim
Psychiatric confusion, abnormal
dreams, dizziness

Propafenone,
Pecinidine,
Amiodarone,
Verapamil,
Diltiazem,
Nifedipine, ↑
Captopril,
Cyclosporin
Pharmacodynamic
β-blockers,
Verapamil, Diltiazem, • ↓ Cardiac contractile state
Flecainide,
Disopyramide
• ↓ SA – AV conduction

Kaluretic, Diuretics,
Sympathomimetic • ↑ Automaticity
drug

Management of Digoxin toxicity

Antidigoxin immunotherapy (fab fragments)

K+

Lidocamil/ Phenytoin
Efek pada Jantung

• Menghambat Na+/K+ - ATP – ASE

Efek mekanik (+) inotropik Indikasi Gagal
Jantung

• ↑ Potensial aksi dini

• ↑ resistensi membrean diikuti
Arterial Fibrilasi ( indikasi)
Efek listrik • ↓ Potensial aksi fase plateas
Arterial Fluter (indikasi)
• ↓ resistensi membran indikasi SVT
• ↑ tonus vagus

Efek pada organ lain

Semua organ eksitase termasuk otot polos & saraf

GIT
SSP
Ginekomastik (perangsangan estrogen)
Anti Arrhytmic drugs
Mechanism of anti arrhythmias drug action
Decreased phase 4 slope
• β blocker

Increased threshold
• Na+ channel blocker
• Ca++ channel blocker

Increased max – diastolic potential

• Adenosine
• Acetylcholine

Increased action potential duration

• K+ channel blocker

Ant arrhythmic drugs can cause arrhythmias

Some arrhythmias should not be treated
Classification of anti arrhythmia drugs
Sodium channel blocker
• Sodium channel (++)
• Diisopyramide, Quinidine, Procainamide
• Blocks K+ Efflux (+)
• Lidocaine, Mexiletine, Tocainide
• Sodium channel (+++)
• Flecainide, Encainide, Propafenone

Anti adrenergic
• β blocker

K+ channel Efflux blockers also Na+ blockers

• Amiodarone
• Sotalol

Ca++ channel blockers

• Verapamil & Diltiazem

Autonomic Effects
• Vagus stimulation
• Digoxin
• Adenosine receptor activation
• Adenosine
Farmakokinetik
O P Dosis Kadar Metab Eks Indikasi Efek samping
puncak
KINIDIN + + 3 X 200 mg 60 – 90’ H G/H AF, SVT
PROKAINAMID + + 3X (250000 – 45 – 70’ H G VES, SVT Lupus like
500) mg syndrome,
leukopeni
DIISOPIRAMID + - 3X 100 mg 60 – 120’ H G VES, SVT Mulut kering,
konstipasi,
penglihatan kabur
LIDOKAIN - + 1 MG/ KG bb H VT (pasca hipotensi
=1mg/ jam miokard infark)

PROPAFENON + + 3 x(150 -300) 60 – 180’ VES

mg

Hipotensi / Sinkop
Kardiovaskular
• SA block
• QRS – Interval • AV block
• Long QT • Torsades de Poentes
• ↑ ventrikuler rate (efek
anti kolinergik)

Cinchonism

• Demam
• Tinitus
• Penglihatn kabur
• Diplopia
• Sakit kepala
• Delirium
• Prikosis
• Gangguan GIT
Amiodaron
Farmakokinetik indikasi Efek samping

O P T1/2 Dosis VT, AF Pro aritmik,

Hipotensi, gangguan fungsi: hati,
+ + 25 – 60 jam Loading 600 tiroid, paru & mata
s/d 800 mg/
hari
Maintenance
300mg/ hari

Sotalol
Farmakokinetik indikasi Efek samping

O P T1/2 Dosis SVT, VT Gagal jantung

+ - 11 jam 800 s/d 320

mg/hari
Bradicardy
Sinus Bradicardy
1. Ephedrine
2. Aminophyline
3. Atropine (I.V.)

Heart Block
1. Atropine (I.V.)
2. Temporary Pacemaker
3. Permanent Pacemaker
Permanent Pacemaker